Disorders of attention are a significant public health problem. Primary attention deficit disorder is estimated to affect 6 to 9 percent of school aged children (Anderson, J. C. et al. Arch. Gen. Psych. 44:69 (1987); Safer, D. J. et al. JAMA 260:2256 (1988)). Well-designed follow-up studies have demonstrated that this disorder is not confined to childhood but is present in up to 50 percent of young adults who have the disorder as children (Mannuzza, S. et al. Arch. Gen. Psych. 50:565; Willens, T. E. et al. In Nadeau, K. Ed. A Comprehensive Guide to Attention Deficit Disorder, Brunne/Mazel, Inc. New York, (1993). This suggests that up to 2 to 4 percent of the adults in the United States may exhibit symptoms of a primary attention deficit disorder. Disorders of attention often lead to poor performance in school and at work and are correlated with antisocial behavior. These behaviors carry a high cost to individuals in lost time and effort, as well as imposing direct costs on society.
Attention disorders are also associated with indirect costs. For example, there is evidence that patients with attention disorders often “self-medicate” in destructive ways. These patients have a higher than average incidence of cigarette smoking and alcoholism. They also have a higher than average incidence of illegal drug use (Barkley, R. A. In Attention Deficit Hyperactivitiy Disorder, Guilford Press, New York, (1990) Chapter 4, pp. 106–129). Thus, an effective treatment for attention disorders would be also be a useful treatment for some substance dependencies.
Current approved treatments for attention deficit disorder are limited to drugs that affect amine metabolism in the brain (Spencer, T. et al. J. Am. Acad. Child Adolesc. Psych. 35:409 (1996)). These drugs have significant limitations including side effects and abuse potential, making currently available treatments controversial. Such medications include the stimulants methylphenidate and dextroamphetamine. Pemoline is another stimulant sometimes used to treat attention deficit disorder in children. These stimulant drugs can have cardiac side effects, which are less pronounced in the case of methylphenidate. These stimulants can also cause growth suppression in children, and are potentially addictive for adolescents and adults.
Current alternatives to stimulants for the treatment of attention disorders are the tricyclic antidepressants and clonidine. The use of tricyclic antidepressants is more likely than the use of stimulants to cause cardiac arrhythmias in children. However, because of the likelihood of stimulant abuse by adolescents and adults with attention disorders, tricyclic antidepressants and clonidine are often tried first (Maxmen, J. S. and Ward, N. G. Essential Psychopathology and Its Treatment, p. 443, Second Edition, Norton & Co., New York, (1995))
Recent studies have shown that nicotine may be an effective treatment for attention deficit disorder (Levin, E. D. et al. Psychopharmacology 123:55 (1996)). However, nicotine acts at multiple pharmacological sites in the body, can be addictive and also has undesirable side effects, and its mode of action is not known. It is not known, for example, which of nicotine's pharmacological effects are responsible for the increased attention displayed by subjects to whom nicotine was administered.
Impaired attention may also be a characteristic of Alzheimer's disease, although Alzheimer's patients typically remain alert (Coyle et al., Alzheimer's Disease: A Disorder of Cholinergic Innervation, Science 219:1184–90 (1983)), and the underlying disorders and known treatments are very different (Grady, C. L. et al. J. Clin. Exp. Neuropsychology 10:576 (1988)). Alzheimer's disease involves progressive and profound loss of memory, postulated to involve a deficiency in brain cortical acetylcholine affecting cholinergic synapses. This deficiency is thought to be caused by selective degeneration of acetylcholine-releasing neurons (Coyle, supra). Disorders of attention and ADD, which are concerned with mental concentration as opposed to memory, are not thought to be caused by acetylcholine defficiencies.
Certain synapses of the brain use acetylcholine as a neural transmitter, to transmit messages across the synapse to a cholinergic receptor. During normal transmission, acetylcholine crosses the synaptic gap to carry the message by stimulating the cholinergic receptor. Memory is thought to be related, at least in part, to post-synaptic changes which occur as a result of the timing and strength of acetylcholine stimulation during learning, with certain experiences tending to block or facilitate corresponding neural pathways, i.e. making it more or less difficult to stimulate the same post-synaptic receptor at a future time. (Deutsch, The Cholinergic Synapse and the Site of Memory, Science 174:788–94 (1971)). Acetylcholine also is rapidly destroyed by the enzyme cholinesterase. Thus, insufficient acetylcholine or excess cholinesterase can interfere with synaptic transmission by too rapidly destroying the acetylcholine message, resulting in weak cholinergic stimulation which can be experienced as memory loss. When this condition is chronic, i.e. from degeneration of acetylcholine-releasing neurons, the Alzheimer's syndrome may develop. One way of counteracting this imbalance is by interfering with the ability of cholinesterase to degrade acetylcholine, as by treatment with a cholinesterase inhibitor (Sugimoto et al., U.S. Pat. No. 4,895,841).
Attention is related to memory in that attention is a prerequisite to memory. Disorders of attention or learning, including ADD, do not typically involve memory loss, and are characterized by symptoms such as motor restlessness, short attention span, poor concentration and organizational skills, impulsive behavior, and lack of task persistence. The cause or causes of ADD is unknown. Several theories have been proposed, and include impaired ability of the frontal lobes to process current experiences and integrate them with memory (frontal lobe disinhibition), as well as abnormalities or imbalances in one or more of dopamine and norepinephrine in the brain (the catecholemine hypothesis). However, studies of these catecholamines in both animals and man, as well as other neurotransmitters such as serotonin, have yielded inconsistent results regarding the biochemical basis for ADD. Although impaired use of dopamine, norepinephrine, and serotonin is implicated in ADD, the underlying neurochemical dysfunction is not well understood, nor are there satisfactory and well-recognized therapies for ADD.
Thus, a need exists for additional therapies which effectively treat disorders of attention generally, and ADD specifically. Therapies which are specific to loss of attention, and which are not addictive, do not promote cardiac imbalance, and do not have other undesirable characteristics are particularly needed.